Delivery of therapeutic drugs into viable epidermis and dermis of the skin can be a challenge due to the barrier properties of the stratum corneum, the outermost layer of the epidermis. The delivery of poorly water soluble drugs into the skin can be even more of a challenge. Skin penetration enhancers have been employed in topical drug formulations to increase the penetration of drugs into the skin and have had some success. However, some penetration enhancers such as solvents and surfactants can be irritating to the skin. Volatile silicone fluids have been employed in topical formulations to increase the penetration of drugs into the skin; however, high concentrations of volatile silicone fluids, i.e., 25% and greater, and/or combinations of volatile silicone fluids with other potential skin irritating compounds such as alcohols, e.g., C1 to C4 aliphatic alcohols, surfactants, other penetration enhancers, and other volatile solvents have been needed to produce the penetration enhancement effect. Additionally, some penetration enhancers will cause the drug to penetrate transdermally and be systemically absorbed, which is not desirable when only treating a condition of the skin (e.g., epidermis and/or dermis). Other topical delivery systems have been employed where the drug is chemically modified with surfactants and other substances, but these materials can also be irritating to the skin.
Taxanes, including paclitaxel and docetaxel, have been used for the treatment of cancer for many years. The cancer treatment formulation initially developed for intravenous (IV) infusion injection, TAXOL® (BMS), is paclitaxel dissolved in a 50:50 v/v mixture of polyethoxylated castor oil (CREMOPHOR® EL) and dehydrated ethanol. However, the systemic use of this formulation results in significant clinical toxicity (Rowinsky et al. 1993). Substantial effort has been devoted to the development of CREMOPHOR EL-free formulations of paclitaxel (Ma and Mumper, 2013). One such formulation is disclosed in U.S. Pat. No. 8,221,779, herein incorporated by reference, which discloses injectable aqueous compositions of antimitotic drug microparticles, including paclitaxel, useful for the treatment of cancers by intraperitoneal and intravenous (IV) injection of the compositions.
However, problems of aqueous based compositions containing drug nanoparticle crystals, including taxanes, is that many times, the drug nanoparticle crystals will grow in the aqueous based compositions while in storage. This is especially problematic for injectable dosage forms, including compositions for (IV) infusion, where the presence of large crystals in the compositions could cause serious harm to the patient.
Psoriasis is a chronic, disfiguring, immune-mediated skin disease affecting approximately 2-4% of the population worldwide (Parisi et al. 2013). This disease is characterized by excessive growth of epidermal keratinocytes and angiogenesis, as well as accumulation of inflammatory cells (Heidenreich et al. 2009; Schon and Boehncke, 2005). Psoriasis can result in erythematous skin lesions (plaques), psoriatic arthritis, and nail dystrophy; furthermore, it is associated with Crohn's disease and other systemic diseases as well as depression, thus causing significant morbidity and contributing to early mortality (Henseler and Christophers, 1995; Mak et al. 2009; Nickoloff and Nestle, 2004).
Anecdotal observations of improvements in psoriasis-afflicted cancer patients receiving paclitaxel led to the hypothesis that taxanes (e.g., paclitaxel, docetaxel) may have the potential to be used as an alternative therapy to treat psoriasis. An open-label, prospective Phase II study conducted in 12 subjects with severe psoriasis concluded that intravenous (IV) infusions of micellar (non-Cremophor EL-containing) paclitaxel over weekly time periods resulted in therapeutic activity in these patients, while being generally well tolerated (Ehrlich et al. 2004). Nonclinical evaluations disclosed in U.S. Pat. No. 6,515,016 demonstrated reduced inflammation, swelling, and erythema in skin inflammation models following treatment with topical paclitaxel. However, topical treatment of psoriasis can be especially problematic because the psoriatic plaque buildup on the skin impedes the delivery of the drug into the skin. Currently, there are no FDA approved topical taxane formulations for the treatment of psoriasis.
Treatment of diseases and conditions of keratinous tissue, including nails, the nail bed, and hair, have been difficult because of the hard protective layer of keratin which inhibits penetration of drugs to the affected tissue. Although nails are a skin appendage, nail diseases are distinct from diseases of the skin. Common diseases of the nail include onychomycosis, a fungal disease, and nail psoriasis, which often affects patients with psoriasis of the skin.